Type I IFNs are a family of cytokines that all signal through an ubiquitously expressed heterodimeric receptor (IFNAR) resulting in antiviral, antiproliferative and immunomodulatory effects. In humans, type I IFN is composed of at least 12 IFNα protein subtypes and 1 subtype each for IFNβ, IFNε, IFNκ, and IFNω. Induction of type I IFN occurs in response to both sterile and microbial ligands. While the antiviral and antiproliferative effects of type I IFN have been exploited in the clinic for infectious disease and oncologic indications, antagonists of type I IFN are being developed for immune-mediated inflammatory indications.
Multiple immune-mediated inflammatory diseases, such as SLE, type I diabetes, psoriasis, primary Sjögren's disease, systemic sclerosis and rheumatoid arthritis, exhibit evidence of elevated type IFN to various degrees as determined by the overabundance of IFN-inducible gene transcripts commonly called the IFN-signature present in whole blood and/or tissue.
Type I IFN antagonist approaches currently in clinical development for lupus include multiple approaches to neutralize IFNα subtypes and not other type I IFNs (β, ε, κ, ω) using anti-IFNα antibodies, such as those described in U.S. Pat. No. 7,087,726, U.S. Pat. No. 8,025,882 and U.S. Pat. Appl. Publ. No. US2008/0160030. Clinical trial data indicates partial reduction of the type I IFN signature in patients treated with anti-IFNα antibodies (Merrill et al., Ann Rheum Dis 70:1905-1913, 2011; Yao et al., Arthritis Rheum 60:1785-1796, 2009) and improvement in signs and symptoms of SLE, flare rates, and steroid burden at week 24 in a pre-specified biomarker defined group of Interferon Signature Metric (ISM)-Low moderate to severely active lupus subjects. No efficacy was seen in patients pre-defined as ISM-High (Kalunian et al., 2012 ACR/ARHP Annual Meeting; Abstract #2622, 2012).
Anti-IFNAR1 antibodies are an alternative to treat lupus (Wang et al., 2013; Clinical Pharmacology & Therapeutics accepted article preview 14 Feb. 2013; doi: 10.1038/clpt.2013.35). IFNAR1 blockade would be predicted to abolish IFN signaling induced by all type I IFNs, including IFNβ. IFNβ may play a more critical role in antiviral defense, as specific deletion of the gene encoding IFNβ incurs substantial susceptibility to a host of viruses when compared to similarly exposed mice having functional IFNβ (Lazear et al., J Virol 85:7186-7194, 2011; Deonarain et al., J Virol 74: 3404-340, 2000; Deonarain et al., Circulation 110: 3540-3543, 2004; Gerlach, et al., J Virol 80: 3438-3444, 2006).
Therefore, there is a need for additional antibodies for the treatment of lupus and other immune-mediated inflammatory diseases.